Metered dose aerosol valve

ABSTRACT

A hand held apparatus and method for creating an aerosolised mist of particles is described. The apparatus comprises a high pressure vessel containing a solution or suspension of the substance to be aerosolised in a high pressure liquefied gas, a manually actuatable valve and a spray nozzle. The high pressure liquefied gas is in a sub-critical state.

This invention relates to a method and apparatus for dispensing amaterial in aerosol form. It is particularly, though not exclusively,concerned with metered dose medicament aerosols, for example metereddose inhalers (MDIs).

BACKGROUND OF THE INVENTION

Aerosol type dispensers are used throughout the world for dispensing awide range of products, for example hair lacquer, furniture polish,cleaners, paint, insect killers and medicaments.

Liquefied compressed gases are invariably used as the propellant foraerosol dispensers for inhalation therapy in preference to non-liquefiedcompressed gasses such as nitrogen or carbon dioxide, as they confer thefollowing critical advantages:

a) the spray undergoes flash evaporation to give aerosols of very smallparticle size

b) the spray particle size remains constant during pack emptying as theinhaler vapour pressure is maintained at an almost constant level byprogressive propellant evaporation

c) the pressure generated by partial evaporation of propellant in thevalve metering chamber causes efficient discharging of the metered valvecontents and accurate dose delivery

d) suitably designed formulations have notably good chemical drugstability and resistance to microbial growth.

FIGS. 1A and 1B of the accompanying drawings show the valve and lowerportion of a typical MDI aerosol dispenser in closed and open positionsrespectively. Such dispensers generally comprise a small aluminiumshuttle valve 1 which is crimp fitted to the can 2 containing the drugand chlorofluorocarbon (CFC) propellants. The valve is activated bymanually pressing shuttle pin 3 such that it moves a small distance intothe can 2. In order to do this it is necessary to overcome the forceexerted on the pin 3 by virtue spring 4 and of the pressure within thecontainer. Pressures within such dispensers are typically around 8 barwhich is sufficient to maintain CFC propellants in a liquid state atambient temperatures.

Until recently, CFCs were the most common of the propellant gases usedin aerosols because they are inert, miscible with a wide range ofproducts, are easily liquefied under low pressures, give a substantiallyconstant product flow-rate, and can produce sprays of droplets havingmean diameters in the range of 3 to over 100 micrometers. However, inthe 1970's it was proposed that CFCs were probably responsible fordepleting the Earth's protective ozone layer, and in 1987, mostcountries signed the Montreal Protocol to phase out the use of CFCs andhave since agreed to stop use of CFCs for non-essential applications bythe end of 1995. One notable exemption to this deadline for cessation ofuse is in relation to MDIs for medicaments, which are regarded as anessential use of CFCs, but even this use of CFCs will be phased out asacceptable alternatives are developed.

Many companies are now working to develop alternative CFC--freepropellants for use in aerosol spray devices including MDIs to overcomethe ozone destructing properties of conventional CFC containingpropellants. A class of propellants which are believed to have minimalozone-depleting effects in comparison to conventional CFCs comprisefluorocarbons and hydrogen-containing fluorocarbons (commonly known asHFA propellants), and a number of medicinal aerosol formulations usingsuch propellant systems are disclosed in, for example European PatentApplication Publication No. 0372777 and PCT Patent Application Nos.WO91/04011 WO91/11173, WO91/11495 and WO91/14422. These applications areall concerned with the preparation of pressurised aerosols for theadministration of medicaments and seek to overcome the problemsassociated with the use of the new class of propellants, in particularthe problems of stability associated with the pharmaceuticalformulations prepared. The applications all propose the addition of oneor more of adjuvents such as alcohols, alkanes, dimethyl ether,surfactants and even conventional chlorofluorocarbon propellants insmall amounts to minimise potential ozone damage. Surfactants are addedto make the suspension formulations stable. However, whilst surfactantsmay conveniently be used in MDIs which use CFC propellants, surfactantsare not generally solvent in HFA propellants and so require the use ofadditional co-solvents.

Attempts have also been made to develop devices which producesatisfactory spray characteristics making use of compressed gases suchas nitrogen and carbon dioxide, which are present in the atmosphere inrelatively large proportions. The main problem associated with aerosoldispensers of this type which use compressed gas propellant is thatwhilst the spray characteristics may be satisfactory when the dispenseris full and the propellant is at a high pressure, they display a seriousdrop in pressure during emptying as the available headspace increaseswith the result that the atomizing and spray pattern deteriorate to anextent that dispensing becomes unsatisfactory for many purposes. Suchdispensers may be used where such deterioration of the atomization andspray pattern are of no concern, e.g. in the dispensing of foodstuffs,but it has not been found to be useful in areas where atomization andspray patterns are important, e.g. in dispensing of medicaments. Forthis latter application it is often required to deliver drugs totopically treat the lung or to provide a route for absorption into theblood stream of drugs that are poorly absorbed from the alimentarytract. To reach the alveoli it is essential that the aerodynamic size ofthe particles is less than 10 micrometers, preferably between 0.5 and 5micrometers. In order to reliably reproduce aerosol sprays from adispenser in which the majority of particles have a size of between 0.5and 5 micrometers it is necessary to maintain a fairly constantpropellant pressure.

The pressures that would be required to maintain gases such as carbondioxide in a liquid state at ambient temperatures are typically of theorder of 10 times greater than that within a conventional dispenser suchas that shown in FIGS. 1A and 1B, and such pressures are far in excessof those within any dispensers currently available. Hence to maintainthe same activation force, the shuttle pin diameter would need to bereduced accordingly resulting in more stringent engineeringrequirements.

U.S. Pat. No. 5,301,664 describes an apparatus for producing a gas-bornedispersion of a physiologically active solute dissolved in asupercritical fluid solvent. The supercritical fluid solution is passedinto a subcritical region to evaporate the solvent and form an aerosolcloud of the solute particles. Some of the problems associated with thisdevice are that: (i) the temperature and pressure of the reservoir mustbe maintained above the critical temperature and pressure of the solventin order to maintain supercritical conditions, and (ii) to ensureconsistent delivery of solute dose upon each actuation of the valve itis necessary to either reduce the reservoir volume each time a dose isdelivered by the magnitude of the volume dispensed to maintain solutedensity, or increase the dose size accordingly.

European Patent Application 675054 (published after the priority date ofthis application) describes a constant quantity injection valve andcanister for carbon dioxide however it does not discuss the use ofsolutions or suspensions of substances in carbon dioxide, nor does itmention use of the valve in an apparatus for inhalation therapy.Furthermore, since opening of the valve requires the pressure inside thecanister to be overcome, the arrangement is disadvantageous when thecarbon dioxide is under very high pressure.

European Patent Application 677332 (published after the priority date ofthis application) describes a method and apparatus for producing fineparticles of substance which comprises dissolving the substance in afirst liquid, mixing the resultant solution with a second fluid (such assupercritical carbon dioxide) and then rapidly lowering the pressure.However this method may not be suitable for all substances and theapparatus is relatively complex since it requires control of a mixingstep. Furthermore, if the solvent of the first liquid is itself solublein the second fluid, the dissolved substance may start to recrystallisein an uncontrolled manner prior to the pressure being lowered.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method andapparatus for generating aerosol mists which overcomes theaforementioned disadvantages or which is of more general application orwhich achieves the desired end with greater ease or simplicity.

According to the present invention there is provided a hand heldapparatus for creating an aerosolised mist of particles, the apparatuscomprising a high pressure vessel containing a solution or suspension ofthe substance to be aerosolised in a high pressure liquefied gas whichis in a sub-critical state, a manually actuatable valve and a spraynozzle.

DETAILED DESCRIPTION OF THE INVENTION

We particularly envisage that the valve will be a metering valve. Thus,the valve may comprise a body having an inlet in communication with thehigh pressure vessel, an outlet in communication with the spray nozzle,and a metering member including a metering chamber mounted in the bodywhich is adapted to move between a first position in which it is incommunication with the inlet and a second position in which it is incommunication with the outlet.

In a preferred embodiment of the invention, the metering member isdefined by a shaft and the metering chamber is a cut-away section of theshaft. Thus the valve body is provided with a bore, the metering memberis defined by a shaft, the metering chamber is a cut-away section of theshaft and the shaft is seated in the bore.

Preferably both ends of the bore will be open to the atmosphere.

In a particularly preferred embodiment of the invention the valvecomprises a body with an inlet and an outlet, a shaft with a cut awaysection mounted in the body and moveable between a first position inwhich the cut away section is in communication with the inlet, and asecond position in which the cut away section is in communication withthe outlet, and wherein the shaft and inlet are arranged such that theforce required to actuate the valve by movement of the shaft between thefirst and second positions is substantially independent of the pressureat the inlet.

Such an embodiment has the advantage that the user of the apparatus willnot have any difficulty in causing actuation of the valve even when thepressure inside the high pressure vessel is very high. More particularlythe pressure that can be tolerated inside the high pressure vessel islimited by the strength of that vessel and the operating parameters ofthe apparatus (for example the requirement to keep the gas in asub-critical state) and not by the strength of the user. Furthermore,the manufacture of apparatus parts is not expected to cause anyparticular engineering difficulty.

In one convenient arrangement which has the advantage of symmetry andease of manufacture, the shaft and inlet are arranged such that thevalve is actuated by movement of the shaft between the first and secondpositions along an axis which is orthogonal to the axis along which thepressure at the inlet is exerted. In the above arrangements, seals willbe disposed between the body and the shaft to prevent the escape ofliquefied gas. Ideally, seals will be arranged such that the inlet is atall times isolated from the outlet irrespective of the position of theshaft. For example there may be disposed 2 pairs of seals such that whenthe metering chamber is in the first position a first pair of sealskeeps the metering chamber in communication with the inlet and isolatedfrom the outlet and when the metering chamber is in the second positiona second pair of seals keeps the metering chamber in communication withthe outlet and isolated from the inlet.

Although a number of alternatives can be envisaged, we find it useful touse polytetrafluoroethylene (PTFE) lip seals with an integral spring.PTFE is a particularly suitable sealing material because it does notabsorb carbon dioxide, does not require lubrication, does not containcarcinogenic compounds and is food grade. PTFE is non-elastomeric and sorequires an integral spring to maintain a seal. Alternative seal designsor materials, e.g. ultra-high molecular weight polyethylene, could alsobe used.

An alternative embodiment of the invention which does not have theadvantage that the force required to actuate the valve by movement ofthe shaft between the first and second positions is substantiallyindependent of the pressure at-the inlet, but which does nonethelesshave the advantage that the burden on the user to actuate the valve maybe significantly eased is set out in the following embodiment.

In this embodiment, we provide an apparatus wherein the valve inlet isprovided with a pin valve comprising a pin biased against a seat and theshaft includes a ramped surface such that in the first position the pinof the pin valve is displaced from its seat to allow communicationbetween the high pressure vessel and the metering chamber and in thesecond position the pin of the pin valve is seated to preventcommunication between the high pressure vessel and the metering chamberand wherein the displacement of the pin from its seat against the biasis caused by urging of the ramped surface against the pin upon movementof the shaft between the first and second positions.

The arrangement is especially convenient when the valve body is providedwith a second outlet and when the shaft includes a second ramped surfacewhich cooperates with the first ramped surface such that the shaft maymove between the first position in which the metering chamber is incommunication with the inlet and the second position in which themetering chamber is in communication with one of the two outlets onmoving the shaft laterally in either direction within the bore.

The apparatus will also desirably be provided with seals which arearranged such that the inlet is at all times isolated from the outlet oroutlets irrespective of the position of the shaft.

As a further improvement, the high pressure vessel may be provided withan integral valve assembly comprising a member biased against a seatsuch that when the high pressure vessel is engaged with the meteringvalve inlet the vessel valve member lies in close proximity to the pinof the metering valve pin valve such that on actuation of the meteringvalve the pin of the metering valve pin valve is pushed off its seat andabuts against the vessel valve member which is in turn pushed off itsseat thereby bringing the inlet into communication with the interior ofthe vessel. The advantage of this arrangement is that the valve of theapparatus may readily be engaged and disengaged from the high pressurevessel thus facilitating replacement or renewal of the contents of thevessel.

According to another aspect of the invention there is also provided amethod for creating an aerosolised mist of particles which comprisesforming a solution or suspension of the substance to be aerosolised in ahigh pressure liquefied gas which is in a sub-critical state and rapidlyexpanding the solution or suspension at the spray nozzle of an apparatusaccording to the invention.

As a consequence of using a high pressure liquefied gas, the propellantwill flash off from the droplets more rapidly than conventionalpropellants thereby decreasing the likelihood that drug laden dropletswill impact on the throat of the patient and, as a consequence, increasethe efficiency with which drug is delivered to the lungs.

High-pressure liquefied gases will typically be those that liquefy atambient temperature at a pressure of greater than 25 bar. More usuallythey will liquefy at a pressure in excess of 55 bar and may be up to 150bar.

As the temperature of a liquid increases, its density decreases whilstas the pressure of a gas increases, its density increases. At thecritical point, the density of both phases becomes the same so that thetwo phases are indistinguishable. By "in a sub-critical state" we meanthat the high pressure liquefied gas will not be become "supercritical"i.e. be above both its critical temperature and pressure (as determinedfrom the phase diagram of the gas) under all useful operating conditionsof the apparatus. For example the pressure of the liquefied gas will notbe so great that the gas becomes supercritical at a temperature belowsay 30° C.

Whilst the critical temperature and pressure are documented forparticular gases, for example:

    ______________________________________                                                                   Critical                                           Gas                 Critical Pressure (bar)                                                              Temperature (° C.)                          ______________________________________                                        Carbon dioxide                                                                             74            31                                                 Nitrous oxide                                                                                       72                    36                                Sulphur hexafluoride                                                                       37                             45                                Ethane                     48                                                                                             32                                Trifiuoromethane                                                                               47                         26                                ______________________________________                                    

these values will tend to be modified by the presence of othercomponents in a formulation containing the liquefied gas.

Gases considered to be especially suitable for carrying out the methodof the current invention include carbon dioxide, nitrous oxide andsulphur hexafluoride. Carbon dioxide and nitrous oxide are the preferredgases, especially carbon dioxide. Mixture of such gases may also beused. Such gases do not deplete atmospheric ozone, act as good solventor suspension media, provide good propellant characteristics for dropletor particle cloud generation, and reduce the need for excipients,especially co-solvents.

Carbon dioxide in liquefied form behaves as a particularly good solventso that surface active agents to stabilise suspensions may be dissolvedtherein without the need for additional co-solvents. Furthermore, uponexpansion into the atmosphere it undergoes substantially instantaneousflash evaporation giving rise to an aerosol mist of the activeingredient with very small particle sizes.

Substances suitable for delivery in this way include pharmaceuticalsespecially pharmaceuticals destined for inhalation such as salbutamol,beclomethasone dipropionate, salmeterol and fluticasone propionate andpharmaceutically acceptable salts thereof. Other pharmaceuticalsdestined for inhalation include cromoglycate, nedocromil, ipratropium,terbutaline, formoterol, budesonide and reproterol and pharmaceuticallyacceptable salts thereof.

Depending on the properties of the active ingredient and its solubilityor otherwise in the liquefied gas propellant, excipients might be usedto improve the formulation characteristics.

In order to improve the properties of a suspension formulation it may bedesired to dissolve or disperse a surfactant in the liquefied gas. Aco-solvent may likewise be included in the liquefied gas in order toimprove the properties of solution or suspension formulations. As towhether a suspension or solution of the substance to be dispensed may bepreferred and the concentrations thereof as well as the use andconcentrations of excipients such as co-solvents, surfactants ordiluents will depend on the solubility and other properties of thesubstance to be dispensed in the propellant.

Preferred embodiments of the invention are described below, by exampleonly, with reference to the accompanying drawings, wherein:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are partial cross-sectional views of the hand-heldapparatus shown in FIG. 2. In FIG. 1A, the valve is in the closedposition. In FIG. 1B, the valve is in the open position.

FIG. 2 shows a plain view of a hand held-apparatus according to theinvention;

FIG. 3 shows a section through a metering valve according to oneembodiment of the invention;

FIG. 4 shows a section through a seal used in the metering valve of FIG.3;

FIGS. 5A-5C show sections through the metering valve of FIG. 3 atdifferent stages during operation of the valve;

FIG. 6 shows a section through a metering valve according to a secondembodiment of the invention; and

FIG. 7 shows a section through a reservoir with an integral valveassembly suitable for use with the metering valve of FIG. 6.

The apparatus according to the invention shown in FIG. 2 comprises ahand held high pressure vessel or reservoir 4 containing a suspension ofsalbutamol sulphate suspended in liquefied carbon dioxide connected to ametering valve 5 with actuating button 6 capable of handling highpressure liquefied gas and being manually actuatable, and a spray nozzle7. The suspension has a concentration of 32 mg salbutamol sulphate in 8mg carbon dioxide, and is maintained at a pressure of around 60 bar.

The high pressure vessel 4 is of the type commonly available as a sourceof high pressure carbon dioxide for soda syphons. The vessel is ofmetallic construction but might also be formed of any other suitablehigh strength material. The vessel may be provided with a rupturableclosure member as is common on soda syphon-type vessels, oralternatively may be provided with a valve arrangement to control flowfrom the vessel. A vessel provided with a valve arrangement is shown inFIG. 7 and is described in more detail below.

The metering valve mechanism is shown in FIG. 3 and includes a body 8with a screw thread for mounting the high pressure vessel at inlet 9.The body 8 might be provided with a piercing element (not shown) forpiercing a rupturable closure on the high pressure vessel or a valveactuating mechanism to open the valve arrangement on the high pressurevessel. The body 8 is formed with a bore therethrough for receiving ashaft 10, and an outlet 11 leading to a spray nozzle (not shown). Fourseals 12, 13, 14, 15 are provided within the bore.

FIG. 4 shows a section through one of the seals which comprises a PTFElip seal 16 with an integral metal spring 17.

The shaft 10 is formed with a cut away section in the form of achamfered groove 18 which in co-operation with the bore delineates themetering chamber. The metering chamber is sized to contain a 50micro-litre dose. However, the size of the metering chamber may bevaried according to the delivery characteristics required.

Two channelled circlips 19, 20 are arranged within the bore to maintainthe spacing between seals pairs 12, 13 and 14, 15, whilst the channelsensure communication between chamfered groove 18 and the inlet 9 andoutlet 11 respectively depending upon the position of shaft 10.

The shaft 10 and inlet 9 are arranged such that the forces exerted onthe shaft by virtue of the pressure in the vessel are in equilibriumsince the effective area presented by the shaft and upon which thepressure acts is the same for both directions of movement of the shaft.The force required to move the shaft is therefore substantiallyindependent of the pressure within the vessel.

FIGS. 5A, 5B and 5C illustrate the operation of the valve mechanism.FIG. 5A shows the valve in the `primed` position in which the highpressure fluid from the reservoir is contained between seals 12 and 14.To meter a quantity of fluid the shaft 10 is moved into the positiondepicted in FIG. 5B. The metered volume is that contained between seals13 and 14 and can be varied by altering the dimensions of the chamferedgroove 18.

The metered volume of fluid may be dispensed out of the outlet 11 bymoving the shaft 10 into the position depicted in FIG. 5C. As thechamfered groove 18 passes seal 14 a path is established to outlet 11for the metered volume of fluid. The high pressure required to maintainthe metered volume of fluid in liquefied form is thus vented to theatmosphere via outlet 11. As a result the liquefied carbon dioxidepropellant undergoes substantially instantaneous flash evaporation as itexpands through the outlet 11. As the propellant flows through outlet 11it carries with it the volume of active ingredient suspended therein,and the flash evaporation gives rise to an aerosol mist of 200micro-grams salbutamol sulphate with particles of a respirable size. Inthe position shown in FIG. 5C the reservoir pressure is contained byseals 12 and 13. Seal 15 ensures that no fluid escapes out of the end ofthe valve mechanism. After delivery of the metered volume of fluid theshaft is moved back into the position depicted in FIG. 5A under theaction of a spring (not shown) and the valve is re-primed and ready foractuation again.

One advantage of using a metering valve of the type described is thatthe force required for operation is substantially independent ofreservoir pressure. The valve can therefore be actuated comfortably byapplication of finger pressure on the end of shaft 10.

An alternative metering valve is illustrated in FIG. 6. The meteringvalve comprises a body 30 with a suitable means for mounting thereservoir (not shown) at inlet 31. The body 30 is also provided with twooutlets 32, 33 for connection to a spray nozzle (not shown), and a borefor receiving shaft 34. A pin valve 36 is located at inlet 31. Shaft 34is formed with two cut away sections of reduced diameter separated bytwo symmetrical conical sections creating ramped surfaces 37, 38. Thesections of reduced diameter and ramped surfaces 37, 38 form a singlechamber 39 within the bore. Seals 40, 41 are provided between bore andshaft 34 to prevent escape of fluid from chamber 39 through the ends ofthe valve mechanism.

To actuate the valve from the position shown in FIG. 6 the user pushesthe shaft 34 in the direction of the arrow. As the shaft 34 moves withinthe bore, seal 41 moves across outlet 33 to seal chamber 39 therefrom,and pin valve 36 is pushed off its seat by the ramped surface 37 soallowing the liquefied solution or suspension to enter chamber 39 fromthe reservoir through inlet 31. As the shaft approaches the end of itstravel ramped surface 38 allows pin valve 36 to close, and as seal 40moves across outlet 32 the metered volume of fluid contained withinchamber 39 is dispensed out of outlet 32.

Due to its symmetrical configuration subsequent actuation of the valveis achieved by pushing the shaft 34 in the reverse direction to thatindicated by the arrow in FIG. 6. The metering and dispensing process isnow exactly the same as that described above, except that the roles ofoutlets 32, 33, ramped surfaces 37, 38 and seals 40, 41 respectively arereversed.

The metering valve illustrated in FIG. 6 might conveniently be mountedto a reservoir with an integral valve assembly which enables saferemoval of the reservoir from the metering valve without allowing escapeof the contents of the reservoir. An example of such a reservoir isdepicted in FIG. 7. The reservoir comprises a high pressure vessel 50with an outlet 51, and a valve arrangement 52 which in a closed positionprevents flow of the reservoir contents out of the outlet 51, and in anopen position allows flow out of the outlet 51.

The valve arrangement 52 includes a valve member 53 which, in the closedposition, seats against valve seat 54 to prevent flow through the valve,and in the open position is pushed off the valve seat 54 in a proximaldirection with respect to the vessel 50 to allow flow past the valvemember 53 and valve seat 54 to outlet 51. The valve member 53 is biassedto its closed position by means of spring 55 and/or the pressure withinthe reservoir such that, unless acted on by an external force, the valvewill remain in the closed position.

When connected to the metering valve of FIG. 6, outlet 51 is mounted atmetering valve inlet 31 such that valve member 53 lies in closeproximity to pin valve 36. Upon actuation of the metering valve, pinvalve 36 is pushed off its seat and abuts against valve member 53 whichin turn is also pushed off its seat, so allowing the contents of thereservoir to enter chamber 39. At the end of the actuation stroke of themetering valve, valve arrangement 52 closes as pin valve 36 and valvemember 53 return to their respective seats. At any time the reservoirmay be removed from the metering valve without allowing escape of itscontents to enable, for example, replacement of the reservoir.Alternatively, valve member 53 and pin valve 36 might be replaced by asingle pin which forms part of valve arrangement 52 and which protrudesbeyond outlet 51 such that upon actuation of the metering valve it ispushed off its seat by direct contact with ramped surfaces 37 and 38.

We claim:
 1. A hand held apparatus for creating an aerosolised mist ofparticles; wherein the apparatus comprises a high pressure vesselcontaining a solution or suspension of the substance to be aerosolisedin a high pressure liquefied gas which is in a sub-critical state, aspray nozzle, and a manually actuatable metering valve for controllingrelease of the contents of the high pressure vessel to the spray nozzle,and wherein the valve comprises a body having an inlet in communicationwith the high pressure vessel, an outlet in communication with the spraynozzle, and a metering member including a metering chamber mounted inthe body, said metering chamber being adapted to move between a firstposition in which the metering chamber is in communication with theinlet and a second position in which the metering chamber is incommunication with the outlet, and wherein the metering chamber iscloser to the outlet when in the second position than when in the firstposition.
 2. An apparatus according to claim 1 wherein the substance tobe aerosolised is a pharmaceutical.
 3. An apparatus according to claim 2wherein the pharmaceutical is salbutamol, beclomethasone dipropionate,salmeterol, fluticasone propionate or a pharmaceutically acceptable saltof any one thereof.
 4. An apparatus according to claim 1 wherein thevalve body is provided with a bore, the metering member is defined by ashaft, the metering chamber is a cut-away section of the shaft and theshaft is seated in the bore.
 5. An apparatus according to claim 4wherein the bore has both ends open to the atmosphere.
 6. An apparatusaccording to claim 4 wherein the shaft and inlet are arranged such thatthe force required to actuate the valve by movement of the shaft betweenthe first and second positions is substantially independent of thepressure at the inlet.
 7. An apparatus according to claim 6 wherein theshaft and inlet are arranged such that the valve is actuated by movementof the shaft between the first and second positions along an axis whichis orthogonal to the axis along which the pressure at the inlet isexerted.
 8. An apparatus according to claim 4 wherein seals are disposedbetween the body and the shaft to prevent the escape of liquified gas.9. An apparatus according to claim 8 wherein seals are arranged suchthat the inlet is at all times isolated from the outlet irrespective ofthe position of the shaft.
 10. An apparatus according to claim 9comprising 2 pairs of seals such that when the metering chamber is inthe first position a first pair of seals keeps the metering chamber incommunication with the inlet and isolated from the outlet and when themetering chamber is in the second position a second pair of seals keepsthe metering chamber in communication with the outlet and isolated fromthe inlet.
 11. An apparatus according to claim 8 wherein the sealscomprise PTFE lip seals with an integral metal spring.
 12. An apparatusaccording to claim 4 wherein the cut-away section is in the form of achamfered groove.
 13. An apparatus according to claim 1 wherein the highpressure liquefied gas comprises carbon dioxide, nitrous oxide orsulphur hexafluoride.
 14. An apparatus according to claim 4 wherein thevalve inlet is provided with a pin valve comprising a pin biased againsta seat and the shaft includes a ramped surface such that in the firstposition the pin of the pin valve is displaced from its seat to allowcommunication between the high pressure vessel and the metering chamberand in the second position the pin of the pin valve is seated to preventcommunication between the high pressure vessel and the metering chamberand wherein the displacement of the pin from its seat against the biasis caused by urging of the ramped surface against the pin upon movementof the shaft between the fist and second positions.
 15. An apparatusaccording to claim 14 wherein the valve body is provided with a secondoutlet and wherein the shaft includes a second ramped surface whichcooperates with the first ramped surface such that the shaft may movebetween the first position in which the metering chamber is incommunication with the inlet and the second position in which themetering chamber is in communication with one of the two outlets onmoving the shaft laterally in either direction within the bore.
 16. Anapparatus according to claim 14 further provided with seals which arearranged such that the inlet is at all times isolated from the outlet oroutlets irrespective of the position of the shaft.
 17. An apparatusaccording to claim 16 wherein the seals are manufactured of PTFE.
 18. Anapparatus according to claim 14 wherein the high pressure vessel isprovided with an integral valve assembly comprising a member biasedagainst a seat such that when the high pressure vessel is engaged withthe metering valve inlet the vessel valve member lies in close proximityto the pin of the metering valve pin valve such that on actuation of themetering valve the pin of the metering valve pin valve is pushed off isseat and abuts against the vessel valve member which is in turn pushedoff its seat thereby bringing the inlet into communication with theinterior of the vessel.
 19. A method for creating an aerosolized mist ofparticles, which comprises(a) providing a hand held apparatus, whereinthe apparatus comprises a high pressure vessel, a spray nozzle, and amanually actuatable metering valve for controlling release of contentsof the high pressure vessel to the spray nozzle; (b) providing a body inthe valve; (c) providing an inlet in the body which communicates withthe high pressure vessel; (d) providing an outlet in the body whichcommunicates with the spray nozzle; (e) providing a metering memberincluding a metering chamber mounted in the body; (f) providing asolution or suspension of a substance to be aerosolized in a highpressure liquefied gas which is in a sub-critical state within the highpressure vessel, (g) moving the metering chamber between a firstposition in which the metering chamber is in communication with theinlet and a second position in which the metering chamber is incommunication with the outlet, wherein the metering chamber is closer tothe outlet when in the second position than when in the first position;and (h) releasing the contents of the metering chamber as an aerosolizedmist.